Approximately 1/3 of the US population over the age of 15 smokes, a behavior that has enormous impact on mortality and morbidity. While about 35% of smokers annually try to quit, only 3% successfully overcome their addiction. Causes of nicotine addiction likely include a variety of genetic and non-genetic factors. Recent advances in genomic technologies and computerized analysis programs have made it possible to discover susceptibility genes for complex traits. The discovery of genes that contribute to the risk of nicotine addiction will accelerate future efforts toward effective treatment and prevention. Major strengths of this project include the large sample size and the complementary genetic designs (sib-pair linkage, pedigree linkage,and association studies). We propose to carry out genomic scans on 1000 sibling pairs and 20 large Utah families in order to provide ample power to detect susceptibility loci. In addition, we will test for association with single nucleotide polymorphisms (SNPs) in candidate genes. Candidate genes will be chosen based on positional linkage evidence, strong physiological rationale, and altered expression after nicotine exposure in mouse microarray analysis. Existing well-characterized samples of heavy smokers from ongoing Lung Health Studies in Utah and ongoing nicotine dependence studies in Wisconsin will be supplemented by ascertainment of additional heavy smokers, light smokers, and non-smokers from the Utah population. Subjects will be given state-of-the-art assessments of nicotine dependence and withdrawal, in addition to other phenotype assessments. Structural modeling will be used for data reduction to define phenotypic factors for genetic analysis. This project takes advantage of existing resequencing, genotyping and analytic capabilities in the Department of Human Genetics.